- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05960773
Decitabine/Cedazuridine (INQOVI), an Oral DNA Demethylating Agent, in Subjects With BAP1 Cancer Predisposition Syndrome and Subclinical, Early-Stage Mesothelioma
Phase II Evaluation of Decitabine/Cedazuridine (INQOVI), an Oral DNA Demethylating Agent in Subjects With BAP1 Cancer Predisposition Syndrome and Subclinical, Early-Stage Mesothelioma
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background:
Mutations involving BRCA1-Associated Protein-1 (BAP1), a nuclear deubiquitinase involved in epigenetic regulation of gene expression, DNA repair, and cellular energetics, have emerged as one of the most common somatic mutations in malignant mesotheliomas.
Germline mutations involving BAP1 predispose individuals to mesotheliomas and a variety of other malignancies including melanomas, as well as lung, renal, gastric, breast, and hepatobiliary carcinomas.
The cancer penetrance of germline BAP1 mutations is nearly 100%, and most patients develop multiple synchronous or metachronous neoplasms.
Mesotheliomas are the most common malignancies diagnosed in subjects with BAP1 Cancer Predisposition Syndrome (CPDS).
Although clinically evident mesotheliomas arising in the context of germline BAP1 mutations tend to be more indolent than more common, sporadic mesotheliomas, the natural history of early-stage mesotheliomas in subjects with BAP1 CPDS is unknown.
Presently there are no established guidelines for the treatment of subclinical malignancies in subjects with BAP1 CPDS.
Epigenetic aberrations including those related to the up regulation of DNA methyltransferases (DNMT) induce genomic instability and enhance the growth and invasion of mesothelioma cells.
Over-expression of DNMT1 also promotes the development of an immunosuppressive tumor micro-environment (TME).
Up-regulation of DNMT1 is an early event during mesothelioma development, and levels of DNMT1 over-expression are associated with poor survival in mesothelioma patients.
Genetic or pharmacologic inhibition of DNMT1 activity induces growth arrest, genomic stress, and apoptosis of mesothelioma cells.
DNMT1 inhibition can reprogram TMEs thereby promoting more effective antitumor immune responses.
Decitabine/cedazuridine is an oral DNMT inhibitor which is FDA approved for patients with myelodysplastic syndromes (MDS).
Conceivably decitabine/cedazuridine therapy can arrest or delay the progression of subclinical/early-stage mesotheliomas in subjects with BAP1 CPDS.
Objective:
To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 CPDS following decitabine/cedazuridine treatment.
Eligibility:
Participants with history of germline BAP1 mutations and histologically confirmed subclinical, early-stage mesotheliomas, with or without other early-stage BAP1-associated malignancies.
The extent of the disease insufficient to warrant approved front-line therapies (surgery, chemotherapy, immunotherapy).
Age (Bullet) 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status 0 1.
Willingness to undergo pre- and post-treatment, minimally invasive thoracoscopy, and/or laparoscopy to assess treatment response.
Adequate cardiac, renal, hepatic, and hematopoietic function.
Design:
Participants with subclinical, early-stage mesotheliomas will undergo baseline imaging studies followed by minimally invasive thoracoscopy and/or laparoscopy to document the extent of the disease and obtain biopsies for pharmacodynamic (PD) endpoints.
Participants will then begin oral decitabine/cedazuridine at a fixed dose and schedule (one capsule taken per day for three consecutive days during the first week of each four-week cycle) and will continue this regimen for six cycles.
Participants will then undergo repeat imaging and minimally invasive thoracoscopy and/or laparoscopy to determine treatment response and obtain tissue for response endpoints.
Participants who experience disease progression or unacceptable toxicities will be removed from the study.
Participants with stable disease or disease regression will be offered an additional 6 months of decitabine/cedazuridine treatment.
Approximately 15 participants will be accrued to this trial.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: David S Schrump, M.D.
- Phone Number: (240) 760-6239
- Email: david_schrump@nih.gov
Study Contact Backup
- Name: Deneise Francis, R.N.
- Phone Number: (240) 858-3974
- Email: deneise.francis@nih.gov
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- Recruiting
- National Institutes of Health Clinical Center
-
Contact:
- National Cancer Institute Referral Office
- Phone Number: 888-624-1937
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
- INCLUSION CRITERIA:
- Participants with history of germline BRCA1-Associated Protein-1 (BAP1) mutations.
- Histologically confirmed by NCI LP subclinical, early-stage (Tx-T1) mesotheliomas.
- Participants with other early-stage BAP1-associated malignancies in addition to subclinical, early-stage mesotheliomas may be eligible for study.
- The extent of the disease (Tx by radiographic imaging) must be insufficient to warrant approved front-line therapies (surgery, chemotherapy, immunotherapy) per standard of care (SOC). Participants with cT1 tumors may be eligible for study if they have been offered and have refused front-line SOC treatment.
- Age >= 18 years.
- Evaluable disease as confirmed by minimally invasive (videoscopic) assessment (thoracoscopy and/or laparoscopy).
- Willingness to undergo pre- and post-treatment minimally invasive thoracoscopy and/or laparoscopy to assess treatment response.
- Willingness to co-enroll on 20C0106 (Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients with BAP1 Tumor Predisposition Syndrome) and/or 06C0014 (Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies) to enable collection/processing of tumor, blood and normal pleura if applicable per PI.
- ECOG performance status 0 - 1
- Adequate pulmonary reserve evidenced by FEV1 and DLCO >= 35% predicted on screening pulmonary function testing (PFTs).
- Oxygen saturation >= 92% on room air by pulse oximetry or >= 92% by arterial blood gas (ABG) (ABG to be drawn if pulse oximetry < 90% on room air) at screening.
Adequate renal, hepatic, and hematopoietic function at screening as defined below:
- leukocytes >= 3,000/microL
- absolute neutrophil count >= 1,500/microL (without transfusion or cytokine support within 2 months prior to study treatment initiation)
- absolute lymphocyte count > 800/microL
- platelets >=100,000/microL and < 1,200,000/microL
- prothrombin time (PT) <=2 seconds above the upper limit of normal (ULN)
- total bilirubin < 1.5 X institutional upper limit of normal OR direct bilirubin <= 1 ULN for participants with total bilirubin > 1.5 ULN
- serum albumin >= 2.0 mg/dL
- aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <= 2.5 X institutional ULN
- creatinine <= 1.6 mg/ml OR creatinine clearance (eGFR) >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal.
- Women of child-bearing potential (WOCBP) and men must agree to use an effective method of contraception (barrier, hormonal, intrauterine device (IUD), surgical sterilization) from the study entry and up to 6 months (women) or 3 months (men) after the last dose of the decitabine/cedazuridine.
- Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 2 weeks after the last dose of the study drug.
- The ability of a participant to understand and the willingness to sign a written informed
consent document.
EXCLUSION CRITERIA:
- Participants with cancers requiring frontline standard of care treatment.
- Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to study treatment initiation), myocardial infarction (< 6 months prior to study treatment initiation), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II, serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism.
- Therapeutic anticoagulation (oral agents and Lovenox, etc., are monitored by factor 10 levels, not PT or partial thromboplastin time (PTT)) within 2 weeks prior to study treatment initiation.
- Active Hepatitis A (HAV), Hepatitis B (HBV) (e.g., HBsAg reactive), or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected) at screening.
- History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
- Other active infections requiring systemic therapy.
- Active COVID infection.
- Immunosuppressive medications within 4 weeks prior to study treatment initiation except non-systemic corticosteroids.
- History of prior treatment with a DNA demethylating agent.
- Pregnancy (confirmed with beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in females of childbearing potential at screening).
- Uncontrolled intercurrent illness or situation that would limit compliance with study requirements.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1/ Arm 1
Decitabine/cedazuridine (35 mg decitabine and 100 mg cedazuridine; PO QD)
|
Decitabine/cedazuridine (INQOVI) oral tablet (35 mg decitabine and 100 mg cedazuridine) taken 3 consecutive days during the first week of every cycle (1 cycle=28-days) for 6 cycles (i.e., 1 course).
Additional 6 cycles (i.e., Course 2) for subjects with stable disease or disease regression.
Max (total) of 2 treatment courses.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 CPDS following decitabine/cedazuridine treatment
Time Frame: baseline, before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit
|
Assessment of thoracoscopy and/or laparoscopy findings demonstrating stability of evaluable disease or improvement compared to baseline
|
baseline, before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To evaluate the safety of decitabine/cedazuridine
Time Frame: before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit
|
Assessment of safety and tolerability as determined by the frequency and severity of adverse events
|
before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit
|
To determine PFS in participants receiving decitabine/cedazuridine
Time Frame: baseline, after every 6 treatment cycles (Course 1 and Course 2), and until date of progression or last visit ending at the time of the safety visit
|
Progression free survival (PFS) determined by RECIST using the Kaplan-Meier method
|
baseline, after every 6 treatment cycles (Course 1 and Course 2), and until date of progression or last visit ending at the time of the safety visit
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: David S Schrump, M.D., National Cancer Institute (NCI)
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Respiratory Tract Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lung Diseases
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Disease Attributes
- Respiratory Tract Neoplasms
- Thoracic Neoplasms
- Lung Neoplasms
- Adenoma
- Neoplasms, Mesothelial
- Pleural Neoplasms
- Disease Susceptibility
- Mesothelioma
- Mesothelioma, Malignant
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Decitabine
Other Study ID Numbers
- 10001549
- 001549-C
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Mesothelioma
-
University of ChicagoNational Cancer Institute (NCI)Active, not recruitingBiphasic Mesothelioma | Epithelioid Mesothelioma | Peritoneal Malignant Mesothelioma | Pleural Biphasic Mesothelioma | Pleural Epithelioid Mesothelioma | Pleural Malignant Mesothelioma | Pleural Sarcomatoid Mesothelioma | Recurrent Peritoneal Malignant Mesothelioma | Recurrent Pleural Malignant Mesothelioma and other conditionsUnited States
-
National Cancer Institute (NCI)CompletedRecurrent Malignant Mesothelioma | Epithelial Mesothelioma | Sarcomatous Mesothelioma | Stage IA Malignant Mesothelioma | Stage IB Malignant Mesothelioma | Stage II Malignant Mesothelioma | Stage III Malignant Mesothelioma | Stage IV Malignant MesotheliomaUnited States
-
National Cancer Institute (NCI)TerminatedEpithelioid Mesothelioma | Sarcomatoid Mesothelioma | Stage IV Pleural Mesothelioma | Recurrent Malignant Mesothelioma | Stage II Pleural Mesothelioma | Stage III Pleural MesotheliomaUnited States
-
National Cancer Institute (NCI)CompletedCediranib Maleate in Treating Patients With Malignant Mesothelioma That Cannot Be Removed By SurgeryRecurrent Malignant Mesothelioma | Advanced Malignant Mesothelioma | Epithelial Mesothelioma | Sarcomatous Mesothelioma | Localized Malignant MesotheliomaUnited States
-
National Cancer Institute (NCI)CompletedRecurrent Malignant Mesothelioma | Advanced Malignant Mesothelioma | Epithelial Mesothelioma | Sarcomatous Mesothelioma | Localized Malignant MesotheliomaUnited States
-
National Cancer Institute (NCI)Active, not recruitingBiphasic Mesothelioma | Epithelioid Mesothelioma | Stage III Pleural Malignant Mesothelioma AJCC v7 | Stage I Pleural Malignant Mesothelioma AJCC v7 | Stage IA Pleural Malignant Mesothelioma AJCC v7 | Stage IB Pleural Malignant Mesothelioma AJCC v7 | Stage II Pleural Malignant Mesothelioma AJCC...United States
-
Mayo ClinicNational Cancer Institute (NCI)CompletedRecurrent Malignant Mesothelioma | Stage IA Malignant Mesothelioma | Stage IB Malignant Mesothelioma | Stage II Malignant Mesothelioma | Stage III Malignant Mesothelioma | Stage IV Malignant MesotheliomaUnited States
-
ProgenaBiomeRecruitingMesothelioma | Mesotheliomas Pleural | Mesothelioma Peritoneum | Mesothelioma Malignant | Mesothelioma; Lung | Mesothelioma; Liver | Mesothelioma; OmentumUnited States
-
NRG OncologyNational Cancer Institute (NCI)TerminatedPleural Biphasic Mesothelioma | Pleural Epithelioid Mesothelioma | Stage I Pleural Malignant Mesothelioma AJCC v8 | Stage IA Pleural Malignant Mesothelioma AJCC v8 | Stage IB Pleural Malignant Mesothelioma AJCC v8 | Stage II Pleural Malignant Mesothelioma AJCC v8 | Stage IIIA Pleural Malignant...United States, Canada
-
National Cancer Institute (NCI)WithdrawnAMG 102, Pemetrexed Disodium, and Cisplatin in Treating Patients With Malignant Pleural MesotheliomaRecurrent Malignant Mesothelioma | Advanced Malignant Mesothelioma | Epithelial Mesothelioma | Sarcomatous Mesothelioma
Clinical Trials on Decitabine/cedazuridine
-
Otsuka Beijing Research InstituteRecruitingMyelodysplastic SyndromesChina
-
M.D. Anderson Cancer CenterGenentech, Inc.; Astex Pharmaceuticals, Inc.RecruitingChronic Myelomonocytic Leukemia | Myelodysplastic SyndromeUnited States
-
Roswell Park Cancer InstituteNational Comprehensive Cancer NetworkRecruitingCastration-Resistant Prostate Carcinoma | Stage IV Prostate Cancer AJCC v8 | Stage IVA Prostate Cancer AJCC v8 | Stage IVB Prostate Cancer AJCC v8United States
-
M.D. Anderson Cancer CenterRecruitingAcute Myeloid Leukemia | Recurrent Acute Myeloid Leukemia | Refractory Acute Myeloid LeukemiaUnited States
-
M.D. Anderson Cancer CenterActive, not recruitingRecurrent Acute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Recurrent Acute Biphenotypic Leukemia | Refractory Acute Biphenotypic LeukemiaUnited States
-
Astex Pharmaceuticals, Inc.Active, not recruitingMyelodysplastic SyndromesSpain, United States, Belgium, Canada, Germany, Italy
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI); Astex Pharmaceuticals, Inc.RecruitingChronic Phase Chronic Myelogenous Leukemia | Philadelphia Chromosome Positive | BCR-ABL1 Positive Chronic Myelogenous Leukemia | BCR-ABL1 PositiveUnited States
-
Astex Pharmaceuticals, Inc.RecruitingAcute Myeloid Leukemia | Myelodysplastic SyndromesSpain, Poland, Bulgaria, Lithuania, Slovakia, Romania
-
Astex Pharmaceuticals, Inc.CompletedAcute Myeloid Leukemia | Myelodysplastic Syndromes | Chronic Myelomonocytic LeukemiaUnited States, Canada, Spain, Hungary, Austria, Czechia, France, Germany, Italy, United Kingdom
-
Astex Pharmaceuticals, Inc.RecruitingAcute Myeloid Leukemia | Myelodysplastic SyndromesSpain, Poland, Bulgaria, Lithuania, Slovakia, Romania